The invention relates to methods for the targeted preparation of lysobactin derivatives by combined chemical and enzymatic modifications. In particular, the invention relates to a method for preparing lysobactin fragment 4-11 by chemical reduction and cleavage of the resultant product by chymotrypsin.
Lysobactin is a cyclic depsipeptide which originates from a screening program for finding novel antibiotics acting in the biosynthesis of bacterial cell walls (O'Sullivan J. et al., J. Antibiot. (1988) 41(12):1740-1744 and Bonner, D. P. et al., J. Antibiot. (1988) 41(12):1745-1751; Tymiak, A. A. et al., J. Org. Chem. (1989) 54:1149-1157). It shows strong activity against Gram-positive aerobic and anaerobic bacteria. An unusual feature is the high number of non-proteinogenic amino acids in the molecule. In addition to the three β-hydroxyamino acids (2S,3R)-β-hydroxyleucine, (2S,3R)-β-hydroxyphenylalanine and (2S,3 S)-β-hydroxyasparagine, the D-amino acids D-leucine and D-arginine as well as allo-threonine also occur. This complexity and the size of the natural product lysobactin are a great hurdle for targeted chemical modifications.